RESEARCH DEVELOPMENT Changes in the regulatory arena that impact on clinical development 23 May 2011
Agenda Voluntary Harmonisation Procedure PIP and Paediatric requirements Changes to EudraCT and European Regulatory Legislation
Voluntary Harmonisation Procedure (VHP) The Clinical Trials Directive 2001/20/EC aimed to harmonize the conduct of clinical trials within EU Member States (MS) However transposition of the Directive into national legislation led to differing practices, e.g: Distribution of duties between the national competent authorities (NCAs) and ethics committees (ECs) Content, format or language requirements Timelines for review Different application dates by Sponsor in different MS Workload versus number of applications per MS This can lead to differing decisions across MS, potentially jeopardizing the scientific value of the clinical trial
Voluntary Harmonisation Procedure (VHP) cont d The Clinical Trials Facilitation Group (CTFG) was created to coordinate implementation of the EU CT Directive CTFG has proposed a voluntary harmonization procedure (VHP) for the assessment of multinational clinical trials (MN-CTs) to be completed prior to the national review process The initial pilot phase of the process was carried out in 2009 and based on the results of this, the process has been streamlined, pilot phase enlarged and the timelines shortened The VHP consist of 3 phases: Phase 1 request of VHP Phase 2 assessment Phase 3 national step
Day 1-30: Voluntary Harmonisation Procedure (VHP) cont d VHP assessment begins If no questions from the MS, or grounds for non-acceptance (GNA) then the Participating NCAs (P-NCA) will inform the VHP Committee (VHP-C) will issue a statement to the Applicant that the P-NCAs unanimously consider the CTA acceptable If there are questions, or GNA, then a consolidated response will be sent to the Applicant by Day 30, with the expectation that a response from the Applicant is received by Day 40 Day 40-60: The Applicant s response is then sent to the P-NCAs. Within 7 days the VHP-C compiles the assessment of the P-NCAs. If consensus is achieved, the application is considered approved by Day 50 If not, then a teleconference is organized to attempt to reach consensus. Any outstanding issues from P-NCAs are forwarded to the Applicant. If there is consensus that the CTA isn t approvable, the Applicant will be informed by Day 60 with the GNA and possible solutions
Voluntary Harmonisation Procedure (VHP) cont d Phase 3 National step The acceptability statement following the VHP does not imply that the MN-CT is authorised by the P-NCAs. Once the applicant has been notified that the CTA is considered acceptable, a CTA has to be submitted in each participating MS The cover letter should detail that the trial has undergone VHP and the approval attached. Generally the CTA will be accepted as long as no changes have been made The Applicant can decide to not include all P-NCAs in this step (in the case where they had GNA). The Applicant should submit within 20 days of VHP approval. Approval should be received within 10 days as long as the documents are identical The applicant should notify a list of the dates of authorisation of the MN- CT to the VHP-C, when available
Voluntary Harmonisation Procedure (VHP) cont In conclusion there have been differing opinions on whether or not this new procedure has in actual fact reduced timelines and streamlined the clinical trail application process across Europe At a glance it appears to add to the application workload as there now has to be a central submission as well as the national submissions The national competent authorities do not seem to adhere to the stipulated 10 days review time for the national applications Chiltern have been requested by 3 sponsors to try the new system
Paediatric Investigational Plan (PIP) All clinical trial applications are required to include reference to a PIP The sponsor should apply to the Paediatric Committee (PDCO) of EMA for approval of the PIP Should the medication not be relevant in a paediatric population a waiver should be sought from the EMA A deferral may also be applied for from the EMA The clinical trial must contained in an agreed Paediatric Investigation Plan (PIP) (it may involve sites in the Community, in third country(ies) or both) The MAA will be required to produce the PIP when applying for an MA and a reminder is provided on the EudraCT website:.
Paediatric Investigational Plan (PIP) cont d The clinical trial is one of those for which information has to be submitted in accordance with article 45 of Regulation (EC) No. 1901/2006 as amended : Article 45(1): By 26 January 2008, any paediatric studies already completed, by the date of entry into force, in respect of products authorised in the Community shall be submitted by the marketing authorisation holder for assessment to the competent authority The clinical trial is one of those for which information has to be submitted in accordance with article 46 of Regulation (EC) No. 1901/2006 as amended: Article 46(1): Any other marketing authorisation holder-sponsored studies which involve the use in the paediatric population of a medicinal product covered by a marketing authorisation, whether or not they are conducted in compliance with an agreed paediatric investigation plan, shall be submitted to the competent authority within six months of completion of the studies concerned. Chiltern are able to assist in the production of the PIP, Waiver or deferral
Recent Changes to EudraCT and Regulatory Legislation New EU Commission legislation (2010/C 82/01 CT-1) brought out in March 2010 Aim was to reduce documentation and amendments submitted to the EU regulatory agencies Still appears to be in the transition phase some countries have adopted it into their legislation and others have not Allows countries to request country specific documentation Defines the need to submit Substantial Amendments for approval Defines the fact that Non-Substantial amendments should not be submitted Could cause problems with IP release due to inconsistency with documents and information submitted and approved between countries If all countries adopted the legislation it would reduce the documentation required and number of amendments
EU Clinical Trials Register The EU Clinical Trials register is now live and information regarding the clinical trials is within the public domain The EU Clinical Trials Register website allows the public to search for information on clinical trials in European Union (EU) member states and the European Economic Area (EEA) and clinical trials which are conducted outside the EU/EEA if they form part of a Paediatric Investigation Plan (PIP) Website: https://www.clinicaltrialsregister.eu/index.html Historical data (information entered into the EudraCT database between 1 May 2004 and the release of version 8.0 of the EudraCT database on 10th March 2011) will be gradually published online from 22 March 2011
EU Clinical Trials Register Users can find information on the design of trial, sponsor, investigational medicinal products, therapeutic areas and the status of the clinical trial Information available mirrors that provided within the EudraCT form If further information is required, users can contact the sponsor using information listed on site The EMA will not be able to provide any information on a specific clinical trial Current statistics of the information available are: Number of clinical trials in EU Clinical Trials Register: 13,073 Number of clinical trials with subjects less than 18 years old: 2,779